Aberrant angiogenesis plays a critical role in the pathogenesis of numerous diseases, including malignant, ischemic, inflammatory and immune disorders. Numerous cytokines and growth factors that stimulate angiogenesis, such as VEGF, FGF-2, PDGF, IGF-1, TGF, TNF-α, G-CSF have been identified, among which, Vascular Endothelial Growth Factor (VEGF) plays a central role in angiogenesis. VEGF, also known as VEGF-A, was initially identified for its ability to induce vascular permeability and to promote vascular endothelial cell proliferation. VEGF is encoded by a single gene that gives rise to four isoforms by alternative splicing. All four isoforms share the same long and GC rich 5′-UTR, as well as a 3′-UTR that includes multiple RNA stability determinants.
VEGF expression is regulated by a number of factors and agents including cytokines, growth factors, steroid hormones and chemicals, and mutations that modulate the activity of oncogenes such as ras or the tumor suppressor gene VHL. The stability and translation efficiency of the VEGF transcript are influenced by sequences in the 5′- and 3′-UTRs. The 5′-UTR contains an internal ribosomal entry site (IRES) and mediates cap-independent translation initiation while the 3′-UTR harbors multiple AU-rich (AUR) stability determinants that have been reported to regulate turnover of VEGF mRNA.
Translation initiation of the VEGF transcript is uniquely regulated. Under hypoxic conditions, translation of most cellular transcripts mediated by cap-dependent translation initiation process is greatly impaired. Initiation of translation of the VEGF mRNA, however, is mediated via the IRES within the VEGF 5′-UTR under hypoxic conditions. Thus, this form of post-transcriptional regulation permits cells to produce large amounts of VEGF protein to support, for example, tumor growth or aberrant neovascularization in ocular diseases under hypoxic conditions. The stability of VEGF mRNA is also enhanced as a consequence of the binding of factors to elements in the 3′-UTR.
Inhibition of VEGF production may reduce angiogenesis and permit treatment of various disease states that are associated with aberrant angiogenesis. As such, there is a need to develop and characterize mechanisms by which VEGF production may be inhibited, including inhibition of VEGF translation.
Small molecules may inhibit VEGF production. Consequently, there is a need to develop, characterize, and optimize small molecules that inhibit translation of the VEGF gene. These molecules may be useful as anti-angiogenesis drugs, including as drugs for treatment of cancer and other pathologies where aberrant vascularization occurs.
All documents referred to herein are incorporated by reference into the present application as though fully set forth herein.